It has been well established that adult mammalian cardiomyocytes lack significant replicative potential. Thus, myocyte loss in response to ischemic injury results in the formation of scar tissue and leads to insufficient cardiac function that is typically irreversible.
Recent evidence suggests that some cardiomyocytes in the diseased human heart have been found to re-enter the cell cycle in an attempt to compensate for the lost myocytes (Beltrami et al. (2001) N Engl J Med 344(23), 1750-1757). However, this process is thought to be inadequate in countering the massive myocyte loss seen after myocardial infarction. Thus, cell replacement strategies utilizing transplantation of exogenous cells have been studied. Bone marrow derived hematopoietic stem cells (BMCs) have been shown to exhibit the potential to differentiate into cardiomyocytes following transplantation (Jackson et al. (2001) J Clin Invest 107(11), 1395-1402, Orlic et al. (2001) Proc Natl Acad Sci USA 98, 10344-10349; Orlic et al. (2001) Nature 410(6829), 701-705). However, recent studies (Balsam et al. (2004) Nature 428(6983), 668-673; Murry et al. (2004) Nature 428(6983), 664-668; Nygren et al. (2004) Nat Med 10(5), 494-501) have rigorously challenged the conclusions of these reports by independently demonstrating that BMCs transplanted into damaged hearts could not give rise to cardiomyocytes. Balsam et al. ((2004) Nature 428(6983), 668-673) have shown that not only do BMCs fail to give rise to cardiomyocytes, they actually develop into different blood cell types, despite being in the heart. The beneficial effects noted in earlier studies in terms of ventricular performance are thought to possibly be at least partially attributable to angioblast mediated vasculogenesis (Kocher et al. (2001) Nat Med 7)4) 430-436) which could prevent apoptosis of native cardiomyocytes rather than by direct myogenesis.
Side-population (SP) cells have stem cell characteristics as they have been shown to contribute to diverse lineages (see generally Challen and Little (2006) Stem Cells 24(1), 3-12). It has been found that SP cells can serve as progenitors for hematopoietic cells, skeletal muscle, and endothelium (see e.g., Asakura and Rudnicki (2002) Exp Hematol; Gussoni et al. (1999) Nature 401(6751), 390-394; Jackson et al. (2001) J Clin Invest 107(11), 1395-402). SP cells have been identified in the bone marrow as well as in nonhematopoietic tissues, including skeletal muscle, mammary gland, heart, liver, brain, kidney and lung (see e.g., Asakura, et al. (2002) J Cell Biol 159, 123-134; Welm et al. (2002) Dev Biol 245, 42-56; Martin et al. (2004) Dev Biol 265(1), 262-275; Summer et al. (2003) Am J Physiol Lung Cell Mol Physiol 285, L97-L104). SP cells have been identified in several species including mice, rhesus monkeys, swine and humans (SEE E.G., Goodell et al. (1997) Nat Med 3(12), 1337-1345; Storms et al. (2000) Blood 96(6), 2125-2133; Uchida et al. (2001) J Clin Invest 108(7), 1071-1077). In a recent study it was demonstrated that as few as 2000-5000 SP cells isolated from adult bone marrow were able to reconstitute the irradiated mdx mouse bone marrow (Gussoni et al. (1999) Nature 401(6751), 390-394). In another study, as few as 100 skeletal muscle SP cells were shown to reconstitute the entire bone marrow of a lethally irradiated mouse (Jackson et al. (1999) Proc Natl Acad Sci USA 96, 14482-14486). Another recent study demonstrated the adult heart contains SP cells capable of proliferation and differentiation, and that these cells are capable of participating in myocardial repair after cryoinjury is induced in the mouse heart Martin et al. (2004) Supplement to Circulation 110(17), 811).
Thus, there exists the need for therapeutic cell replacement strategies utilizing transplantation of autologous and/or exogenous cells for the treatment of heart disease.